Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes.

The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.

Taurine deficiency as a driver of aging.

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

Microdose lithium reduces cellular senescence in human astrocytes - a potential pharmacotherapy for COVID-19?

Cell senescence is a process that causes growth arrest and the release of a senescence associated secretory phenotype (SASP), characterized by secretion of chemokines, cytokines, cell growth factors and metalloproteases, leading to a tissue condition that may precipitate cancers and neurodegenerative processes. With the recent pandemic of coronavirus, senolytic drugs are being considered as possible therapeutic tools to reduce the virulence of SARS-CoV-2. In the last few years, our research group showed that lithium carbonate at microdose levels was able to stabilize memory and change neuropathological characteristics of Alzheimer's disease (AD). In the present work, we present evidence that low-dose lithium can reduce the SASP of human iPSCs-derived astrocytes following acute treatment, suggesting that microdose lithium could protect cells from senescence and development of aging-related conditions. With the present findings, a perspective of the potential use of low-dose lithium in old patients from the "high risk group" for COVID-19 (with hypertension, diabetes and chronic obstructive pulmonary disease) is presented.

A Caenorhabditis elegans Model Elucidates a Conserved Role for TRPA1-Nrf Signaling in Reactive α-Dicarbonyl Detoxification.

Reactive α-dicarbonyls (α-DCs), like methylglyoxal (MGO), accumulate with age and have been implicated in aging and various age-associated pathologies, such as diabetic complications and neurodegenerative disorders like Alzheimer's and Parkinson's diseases. Evolutionarily conserved glyoxalases are responsible for α-DC detoxification; however, their core biochemical regulation has remained unclear. We have established a Caenorhabditis elegans model, based on an impaired glyoxalase (glod-4/GLO1), to broadly study α-DC-related stress. We show that, in comparison to wild-type (N2, Bristol), glod-4 animals rapidly exhibit several pathogenic phenotypes, including hyperesthesia, neuronal damage, reduced motility, and early mortality. We further demonstrate TRPA-1/TRPA1 as a sensor for α-DCs, conserved between worms and mammals. Moreover, TRPA-1 activates SKN-1/Nrf via calcium-modulated kinase signaling, ultimately regulating the glutathione-dependent (GLO1) and co-factor-independent (DJ1) glyoxalases to detoxify α-DCs. Interestingly, this pathway is in stark contrast to the TRPA-1 activation and the ensuing calcium flux implicated in cold sensation in C. elegans, whereby DAF-16/FOXO gets activated via complementary kinase signaling. Finally, a phenotypic drug screen using C. elegans identified podocarpic acid as a novel activator of TRPA1 that rescues α-DC-induced pathologies in C. elegans and mammalian cells. Our work thus identifies TRPA1 as a bona fide drug target for the amelioration of α-DC stress, which represents a viable option to address aging-related pathologies in diabetes and neurodegenerative diseases.